The objective of this proposal is to identify biochemical parameters and relationships that are associated with the cytotoxicity of a variety of nucleoside analogs. These factors will be monitored in tumor cells and host mouse tissues in order to develop a rational basis for drug dose levels and schedules of administration that would produce the maximal therapeutic benefit in model systems. The compounds of interest are: arabinosyladenine, arabinosyl-1-fluoroadenine, arabinosylcytosine, xylosyladenine, and 2'-deoxyribosyl-2-chloroadenine. Biochemical parameters to be studied that reflect the action of these drugs are: formation and retention of the active nucleoside triphosphate metabolites, the effects of these triphosphates on cellular macromolecular synthesis, the activities of specific enzymes and enzymatic processes, interactions with natural nucleotides, incorporation into nucleic acids and the induction of aberrations in nucleic acid synthesis. The ultimate goal of this project is to develop and understanding of the biochemical and pharmacological basis for successful experimental chemotherapy. This knowledge could form the foundations upon which the rational construction of protocols for clinical trial of these and other drugs studied in a similar manner will be built.